1.4;3.6-Dianhydrohexitol nitrates substituted by purine bases, and pharmaceutical compositions

ABSTRACT

1.4;3.6-Dianhydrohexitol nitrates substituted by purine bases, namely, adenyl-desoxy-1.4;3.6-dianhydrohexitol nitrates of the general formula Ia as well as theophyllinyl-desoxy-1.4;3.6-dianhydrohexitol nitrates of the general formula Ib, ##STR1## wherein R 1  and R 2  are the same or different and, independently of one another signify 
     (a) a hydrogen atom, 
     (b) a straight-chained or branched alkyl group with 1 to 7 C-atoms, 
     (c) an ω-phenylalkyl group, whereby the alkyl group has 1 to 7 C-atoms and whereby the phenyl ring can be halogen-substituted in the p-position, or wherein 
     (d) R 1  signifies one of the residues given under (a) to (c) and R 2  an acyl radical or an aliphatic, possibly methyl-substituted monocarboxylic acid with 2 to 7 C-atoms, or wherein 
     (e) R 1  and R 2 , together with the nitrogen atom to which they are bound, represent the residue of a cyclic, non-aromatic, secondary amine possible containing a further hetero atom, 
     as well as their physiologically acceptable acid-addition salts. 
     Process for the preparation of said compounds and pharmaceutical compositions containing said compounds.

This is a divisional application of application Ser. No. 285,406, filedJuly 20, 1981, now U.S. Pat. No. 4,479,951.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention concerns 1.4;3.6-dianhydrohexitol nitrates substituted bypurine bases, namely, adenyldesoxy-1.4;3.6-dianhydrohexitol nitrates ofthe general formula Ia, ##STR2## as well astheophyllinyldesoxy-1.4;3.6-dianhydrohexitol nitrates of the generalformula Ib: ##STR3##

2. Description of the Prior Art

The basic structure of these compounds consists of one of thestereoisomeric 1.4;3.6-dianhydrohexitols convertible into one another byepimerisation, namely, either 1.4;3.6-dianhydro-L-iditol (="isoidide")(II), ##STR4## in which the OH groups in the 2- and 5-position each havethe exo-configuration, or 1.4;3.6-dianhydro-D-glucitol (="isosorbide")(III) ##STR5## which has an exo-standing and an endo-standing OH groupand thus--in the case of various substituents in the 2- and5-position--occurs in two isomeric forms.

Finally, the basic structure of some intermediate products consists of1.4;3.6-dianhydro-D-mannitol (="isomannide") (IV), ##STR6## which hastwo endo-standing OH groups.

Since, in contradistinction to the glucitol derivatives, in the case ofthe iditol and mannitol derivatives a difference between the 2- and5-substituents is not possible because the C² atom, in the case ofrotation of the molecule through 180°, becomes the C⁵ atom, referencesto the 5-position or 2-position of substituents is, in the case of thesederivatives, superfluous. However, for a better comparison of thestructures of the individual compounds with the general formulae, theisoidide derivatives are here all referred to as 5-purinylisoididederivatives since they result from isosorbide derivatives acylsubstituted in the 5-position. Correspondingly, the isomannide acylderivatives used as starting compounds are referred to as2-acylisomannide derivatives since the 2-purinylisosorbide derivativesare prepared from them.

A brief summary of the stereoisomerism of the 1.4;3.6-dianhydrohexitolsis given by J. A. Mills in Advances in Carbohydrate Chem., 10, 1-53(1955).

Furthermore, the invention is concerned with processes for thepreparation of the initially mentioned 1.4;3.6-dianhydrohexitolmononitrates substituted by purine bases, as well as pharmaceuticalcompositions which contain the compounds according to the invention.

The nitrates of 1.4;3.6-dianhydro-D-glucitol (also called1.4;3.6-dianhydro-D-sorbitol) are known e.g. from U.S. Pat. No.3,886,186, namely, not only in the 2- and 5-mononitrates but also the2,5-dinitrates of isosorbide. These nitrates, especially the dinitrate,which is already commercially available as a medicament, arepharmacologically-active substances with haemodynamic, vasodilatory andanti-aginous effectiveness, which are used especially in the case ofcoronary insufficiency and for the treatment of angina pectoris.

The pharmacokinetics of the dinitrate and of the mononitrates ofisosorbide, isomannide and isoidide have been described by Bogaert andRosseel in Naunyn-Schmiedeberg's Arch. Pharmacol., 275, 339 (1972).

However, it has been shown that the nitrates cause unpleasant sideeffects, especially headaches. Furthermore, the mononitrates are morepoorly resorbed than, for example, isosorbide dinitrate (ISDN). It isalso to be added that the dinitrates of isosorbide, isomannide andisoidide can only be prepared and handled with special precautionarymeasures, since they are explosive.

Thus, there is a need for the making available of new pharmaceuticalagents with the same activity spectrum but which do not display thementioned disadvantages and for the provision of new1.4;3.6-dianhydrohexitol mononitrates which can be used as activecomponents of such pharmaceutical agents.

The task forming the basis of the invention consists in satisfying thementioned need, the solution of this problem in the making available ofthe substances according to the invention.

SUMMARY OF THE INVENTION

Consequently, the subject of the invention are:

1. 5-(9-adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrates(=2-(9-adenyl)-2-desoxy-1.4;3.6-dianhydro-L-iditol 5-nitrates) of thegeneral formula Ic, ##STR7## wherein R¹ and R² are the same or differentand, independently of one another represent

(a) a hydrogen atom,

(b) a straight-chained or branched alkyl group with 1-7 C-atoms,

(c) an ω-phenylalkyl group, whereby the alkyl group has 1 to 7 C-atomsand whereby the phenyl ring can be halogen-substituted in thep-position, or wherein

(d) R¹ signifies one of the residues given under (a) to (c) and R² anacyl residue of an aliphatic, possibly methyl-substituted monocarboxylicacid with 2 to 7 C-atoms, or wherein

(e) R¹ and R², together with the nitrogen atom to which they are bound,represent the residue of a cyclic, non-aromatic secondary amine possiblycontaining a further hetero atom,

as well as their physiologically acceptable acid-addition salts.

2. 2-(9-Adenyl)-2-desoxy-1.4;3.6-dianhydro-D-glucitol 5-nitrates of thegeneral formula Id, ##STR8## wherein R¹ and R² possess the meaningsgiven under (1.), as well as their physiologically acceptableacid-addition salts.

3. 5-(9-Adenyl)-5-desoxy-1.4;3.6-dianhydro-D-glucitol 2-nitrates of thegeneral formula Ie, ##STR9## wherein R¹ and R² possess the meaningsgiven under (1.), as well as their physiologically acceptableacid-addition salts.

4. 5-(7-Theophyllinyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate(=2-(7-theophyllinyl)-2-desoxy-1.4;3.6-dianhydro-L-iditol 5-nitrate), aswell as its physiologically acceptable acid-addition salts.

5. 2-(7-Theophyllinyl)-2-desoxy-1.4;3.6-dianhydro-D-glucitol 5-nitrate,as well as its physiologically acceptable acid-addition salts.

The compounds according to the invention possess coronaryflowthrough-increasing, spasmolytic and blood pressure-loweringeffectiveness. They are suitable for the treatment of coronary diseases,for the treatment and prophylaxis of attacks of angina pectoris, for theafter-treatment of heart infarcts and for the treatment of cardiacinsufficiencies. The new compounds possess a good therapeutic range. Theoral absorption is especially good and the period of action long.Furthermore, they bring about an improvement of the peripheral bloodflow and of brain blood flow.

The handling and preparation of the compounds according to the inventionis less dangerous than, for example, in the case of the known ISDNbecause they are not explosive.

DESCRIPTION OF THE PREFERRED EMBODIMENT

In the 1.4;3.6-dianhydrohexitol basic structure, the compounds accordingto the invention possess 4 asymmetrical C-atoms and are present inoptically-active form since, as starting product, optically pure1.4;3.6-dianhydrohexitols are used which are easily obtainable fromnaturally-occurring sugar alcohols.

The compounds according to the invention can be prepared starting fromthe epimeric, unsubstituted 1.4;3.6-dianhydrohexitols, thus startingfrom L-isoidide, D-isosorbide and D-isomannide, whereby, in the case ofD-isosorbide as starting compound, two different synthesis routes arepossible.

According to the invention, the first route consists in that thecorresponding 1.4;3.6-dianhydrohexitol is converted with a sulphonicacid chloride, preferably with methanesulphonic acid chloride ortoluenesulphonic acid chloride, in a suitable anhydrous solvent and inthe presence of an adjuvant base, preferably in pyridine or inchloroform/triethylamine, at reduced temperature, preferably between-20° and +10° C., into the correspondingmono-O-acyl-1.4;3.6-dianhydrohexitol and the acyl derivative is reactedwith the alkali metal salt, usually the sodium or potassium salt, of thedesired purine derivative, preferably of adenine,6-N-substituted-adenine, theophyllin, 6-methyl-mercaptopurine or6-chloropurine, in a dipolar aprotic solvent, e.g. dimethylformamide,dimethyl sulphoxide, tetramethylurea, diethers of ethyleneglycol,preferably in dimethylformamide or dimethyl sulphoxide, at an elevatedtemperature, preferably at 80° to 130° C., under an inert gas atmosphere(N₂ or Ar).

The exchange of the mesylate or tosylate group by the adenyl,6-N-substituted adenyl, theophyllinyl, 6-chloropurinyl or6-methylmercaptopurinyl radical taking place in this first step takesplace in the manner of reaction of a typical bimolecular nucleophilicsubstitution (S_(N) 2 reaction), which always involves a reversal of theconfiguration on the central carbon atom. This reversal ofconfiguration, which is also known to the expert under the terms"inversion" or "Walden inversion", is the reason why, from the1.4;3.6-dianhydro-D-glucitol 5-acyl derivative, in which the acylradical is present in the 5-endo-position, there always results the1.4;3.6-dianhydro-L-iditol derivative substituted in the 5-position bythe adenyl, 6-N-substituted-adenyl, theophyllinyl, 6-chloropurinyl or6-methylmercaptopurinyl radical, in which the substituent entering intothe molecule in place of the acyl radical no longer stands in theendo-position but rather in the exo-position. The Walden inversioninvolved with the S_(N) 2 reaction is, in entirely the correspondingmanner, responsible for the fact that from the corresponding iditolacylate there always results the glucitol derivative endo-substituted inthe 5-position and from the mannitol acylate the corresponding glucitolderivative exo-substituted in the 2-position.

Thus, completely analogously, from the1.4;3.6-dianhydro-D-glucitol-2-acylate, in which the acyl radical ispresent in the exo-position, there should result the corresponding2-purinyl-1.4;3.6-dianhydro-D-mannitol derivative in which the purineradical should then be endo-standing. However, it has been shown thatthis reaction, thus the substitution of the 2-exo-acyl radical by thevoluminous purine radical, as a result of steric hindrance, does nottake place under the conditions employed according to the invention.

The compounds resulting in the hitherto described first step of thefirst synthesis route have, in the 6-position of the purine ring systemin the case of adenine, an unsubstituted amino group, in the case ofmethylmercaptopurine the CH₃ S-- group and in the case of chloropurinethe chlorine residue. The 6-N-substituted adenyl derivatives are,starting from the 6-methylmercapto- or 6-chloropurine derivatives, whichthus represent valuable intermediate products for the preparation of thecompounds according to the invention, prepared in that one reacts themethylmercapto- or chloropurine derivative with the desired primary orsecondary alkylamine with a straight-chained or branched alkyl groupwith 1 to 7 C-atoms or an ω-phenylalkylamine with an alkyl group of 1 to7 C-atoms or a corresponding ω-phenylalkylamine in which the phenyl ringis halogen-substituted in the p-position, thus, for example withp-chlorobenzylamine, p-chlorophenylethylamine,p-chlorophenylpropylamine. The purine derivatives substituted in the6-position with a heterocyclic secondary amine are obtained from thecorresponding methylmercapto- or chloropurine derivatives by reactionwith the corresponding cyclic, non-aromatic secondary amines possiblycontaining a further hetero atom, for example with pyrrolidine,piperidine, piperazine, morpholine or any of their substitutedderivatives. In an analogous manner, the unsubstituted adenyl derivativecan be obtained by reaction of the 6-chloro- or 6-methylmercaptopurinylderivative with ammonia.

The reaction of the methylmercapto- or chloropurine derivatives withammonia, the desired primary or secondary alkylamine, possiblyp-chloro-substituted ω-phenylalkylamine or cyclic non-aromatic secondaryamine possibly containing a further hetero atom takes place at anelevated temperature and increased pressure, preferably at a temperatureof 100°-170° C. and a pressure of 2-50 ats., especially advantageouslyat a pressure of 2-20 ats., under an inert gas atmosphere (N₂ or Ar),whereby ammonia or the corresponding amine are used in excess,preferably in 2-10 fold molar excess, possibly in the presence of asolvent, e.g. methanol, ethanol, butanol.

Instead of the subsequent substitution of the 6-chloro- or6-methylmercapto group of the purine-1.4;3.6-dianhydrohexitolderivative, the hexitol acylates can, in the first step, also be reactedimmediately, in an analogous manner, with the alkali metal salts of theadenine derivative already correspondingly substituted on the 6-N-atom.Correspondingly substituted adenines, insofar as they are not known fromthe literature, can be obtained from 6-chloro- or 6-methylmercaptopurineby heating with the corresponding amines.

The 5-(7-theophyllinyl)-, 5-(9-adenyl)- and5-(6-N-substituted-9-adenyl)-isohexide derivatives resulting in thecourse of the hitherto described first synthesis route each have a freehydroxyl group in the 2- or 5-position of the 1.4;3.6-dianhydrohexitolring system. This free hydroxyl group is esterified in per se knownmanner with nitric acid, with nitrating acid or with a mixture of nitricacid and glacial acetic acid/acetic anhydride to give the correspondingmononitrates of the general formulae Ia to Ie.

Subsequently, in the case of the 9-adenyl- or6-N-monosubstituted-9-adenylisohexide nitrates, by the reaction thereofwith an acid chloride or anhydride of an aliphatic, possiblymethyl-substituted monocarboxylic acid with 2 to 7 C-atoms, for examplewith pivaloyl chloride, acetic acid chloride, acetic anhydride or thelike, one can prepare the corresponding acyl derivatives in the mannerof a Schotten-Baumann reaction or of the Einhorn variant thereof.

The hitherto described first route according to the invention for thepreparation of the compounds according to the invention, in which thecorresponding isohexide is converted with a sulphonic acid chloride,preferably with methanesulphonic acid chloride or toluenesulphonic acidchloride, into the corresponding monoacyl-1.4;3.6-dianhydrohexitol, hasthe disadvantage that, in the case of the acylation, there results notonly the corresponding 5-O-acyl derivative or 2-O-acyl derivative butsimultaneously also the 2,5-diacyl derivative so that, in the case ofthe isoidide and isomannide derivatives, in each case the monoacylcompound must be separated from the diacylate, whereas in the case ofthe isosorbide, in which two stereoisomeric monoacyl derivatives result,besides the diacylate, the desired acylate must be isolated from themixture of the three acyl derivatives. The separation of the acylatemixture takes place either by fractional crystallisation, fractionextraction or with the help of other per se known methods.

The laborious and time-consuming separation of the acylate mixturedisappears, however, in the case of the use of the second synthesisroute according to the invention to the 5-purinylisoidide derivatives inthat 1.4;3.6-dianhydro-D-glucitol is reacted quantitatively with anexcess of sulphonic acid chloride, preferably methanesulphonyl chlorideor toluenesulphonyl chloride, in pyridine or chloroform/triethylamine,to give the corresponding 1.4;3.6-dianhydro-D-glucitol 2,5-diacylate.

The diacylate is then reacted with the alkali metal salt of adenine,6-N-substituted adenine or theophyllin, under conditions correspondingto those described in the first synthesis route, whereby--because of theabove-described steric hindrance of the substitution in the2-exo-position--only the 5-endo-acylate radical is substituted by thecorresponding purine residue in the case of simultaneous inversion ofthe configuration on the C⁵ -atom. Thus, there results the5-(9-adenyl)-, or 5-(6-N-substituted 9-adenyl)-, or5-(7-theophyllinyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-acylate, whichis saponified by hydrolysis to the corresponding adenyl, substitutedadenyl or theophyllinyl-isoidide derivative and subsequently--in thesame way as in the case of the first synthesis route--is esterified inper se known manner with nitric acid, nitrating acid or with a mixtureof nitric acid and glacial acetic acid/acetic anhydride and is possiblysubsequently acylated on the 6-N-atom analogously to the first synthesisroute.

The degree of steric hindrance in the case of the nucleophilicsubstitution of the 2-exo-acylate group in the isosorbide diacylate istemperature-dependent. In order to obtain the purinyl-isoididemonoacylate as quantitatively as possible from the correspondingdiacylate, one works, therefore, according to the invention, preferablyat a temperature of 80°-100° C. since, at temperatures above 100° C.,the 2-exo-acyl group, even if only to a small extent, is attacked by thepurine derivative employed. As solvents, there are hereby preferablyemployed dimethylsulphoxide or dimethylformamide.

In order to convert the compounds according to the invention into theirphysiologically acceptable salts, there can be used inorganic acids andmineral acids, such as hydrohalic acids and phosphoric acids, as well asorganic acids, such as carboxylic and sulphonic acids, for examplemalonic, succinic, lactic, tartaric, malic, benzoic, salicylic, citric,ascorbic, nicotinic or p-toluenesulphonic acid. The free bases can againbe liberated from the acid-addition salts by treatment with strongbases, for example sodium or potassium hydroxide.

Furthermore, the subject of the invention are pharmaceuticalcompositions which, besides the usual carrier and addition materials,contain at least one of the compounds according to the invention or oftheir physiologically acceptable salts. These compositions can be usedas medicaments in human and veterinary medicine. Conventional carriermaterials are, for example, water, vegetable oils, polyethylene glycols,glycerol esters, gelatine, carbohydrates, such as lactose or starch,magnesium stearate, talc, Vaseline. Conventional additive materials are,for example, preserving, stabilising, lubricating, wetting agents,emulsifiers, physiologically acceptable salts, buffer substances,colouring, flavouring and aroma materials. The selection of the carrierand additive materials depends upon whether the compounds according tothe invention are to be administered enterally, parenterally ortopically.

The compounds according to the invention can also be administered inadmixture with other active materials, for example vitamins or known,commercially-available heart-circulation agents, particularly also withβ-receptor blockers.

EXAMPLE OF A PHARMACEUTICAL COMPOSITION

For the preparation of tablets each of 100 mg. individual weight, eachof which contains 5 mg. of active material, one needs

I. 5 g. 5-(9-adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitratehydrochloride semihydrate

II. 54 g. microcrystalline cellulose

III. 20 g. lactose

IV. 20 g. maize starch

V. 0.5 g. colloidal silicic acid

VI. 0.6 g. magnesium stearate

The substances I-IV are dry mixed for 10 minutes, subsequently themixture is added to the substances V and VI, one mixes for a further 10minutes and presses the so obtained powder on a tabletting machine togive tablets of 100 mg. individual weight.

Each of the compounds and intermediate products according to theinvention mentioned in the following Examples represents an especiallysuitable agent for the preparation of pharmaceutical compositions.

The abbreviations contained in the Examples have the following meanings:

m.p.=melting point (uncorrected)

(decomp.)=decomposition

d=density

[α]_(D) ²⁵ =optical rotation at 25° C., sodium D line.

After the optical rotational values are given the concentrations of themeasured solutions, whereby c 2 means, for example, a concentration of 2g./100 ml. of solution; the solvent is, in each case, given separately.All temperatures are given in °C.

EXAMPLE NO. 1 5-(9-Adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate(a) 1.4;3.6-Dianhydro-D-glucitol 2-methanesulphonate,5-methanesulphonate and 2,5-dimethanesulphonate

To a solution of 4.82 kg. (33 mol) 1.4;3.6-dianhydro-D-glucitol in 24liters of pyridine one adds dropwise, with the exclusion of moisture,stirring and cooling to -15°, within the course of several hours, 3.1liters (40 mol) methanesulphonic acid chloride. Subsequently, onefurther stirs for 15 hours without cooling. One distils off the pyridinein vacuo, adds 15 liters of water to the oily residue, boils up andallows to cool. Suction filtration, washing with 4 liters of water anddrying of the crystalline precipitate gives 2.22 kg. (7.34 mol)1.4;3.6-dianhydro-D-glucitol 2,5-dimethanesulphonate. The filtrate isneutralised, with stirring and water cooling, with about 1.5 kg. sodiumhydroxide and evaporated to dryness at about 70° in a vacuum. The dryresidue is continuously hot extracted with, in all, 30 liters ofchloroform and the extract filtered hot. One allows the extract to standfor 15 hours at 20°, filters off the crystalline precipitate withsuction, washes it twice with 2 liter amounts of chloroform, dries andobtains 2.3 kg. (10.26 mol) 1.4;3.6-dianhydro-D-glucitol5-methanesulphonate. The combined filtrates are evaporated in a vacuumand the residue dissolved hot in 22 liters of ethanol. One leaves tostand for 15 hours at 20°, filters off the crystalline precipitate withsuction, washes it twice with 3 liter amounts of ethanol, dries andobtains 0.65 kg. (2.90 mol) 1.4;3.6-dianhydro-D-glucitol2-methanesulphonate. Evaporation of the filtrate gives 2.21 kg. (9.85mol) of a mixture of the two isomeric monomethanesulphonates which,according to need, can be further separated by repetition of thealternating crystallisations from chloroform and ethanol or, byesterification with methanesulphonic acid chloride in pyridine, iscompletely converted into 1.4;3.6-dianhydro-D-glucitol2,5-dimethanesulphonate. Analytical amounts of the methanesulphonatesgive, after recrystallisation, correct elementary analyses and themelting points and optical rotations set out in Table 1:

                  TABLE 1                                                         ______________________________________                                        1.4;3.6-dianhydro-                                                                         recrystallised                                                                           m.p.                                                  D-glucitol-  from       [°C.]                                                                            [α].sub.D.sup.25                      ______________________________________                                        2-methanesulphonate                                                                        chloroform   135-138.5                                                                             62.5                                                                          (c 2; acetone)                              5-methanesulphonate                                                                        chloroform 123-124   75.9                                                                          (c 2; methanol)                             2.5-dimethane-                                                                             ethanol/   127-128   74                                          sulphonate   acetone              (c 2; acetone)                              ______________________________________                                    

(b) 5-(9-Adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol

Under an atmosphere of nitrogen and with stirring, one adds a solutionof 22.4 g. (0.1 mol) 1.4;3.6-anhydro-D-glucitol 5-methane sulphonate in100 ml. anhydrous dimethyl sulphoxide dropwise at 100° to a suspensionof 15.7 g. (0.1 mol) adenine sodium salt in 200 ml. anhydrous dimethylsulphoxide and then stirs for 8 days at 100°. One distils off thesolvent in vacuo and successively extracts the residue at boilingtemperature with 100 ml. chloroform and n-butanol. The chloroformextract is concentrated to about 300 ml., by the addition of 600 ml.petroleum ether, the crude product is precipitated out and separatedoff; the filtrate is discarded. The butanol extract gives, afterevaporation in vacuo further crude product. The combined crude productsare recrystallised from 400 ml. ethanol. One obtains 9.2 g. (35 mmol)5-(9-adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol. The evaporated motherliquor is dissolved in 200 ml. water and continuously extracted withabout 1 liter of a mixture of chloroform/butanol 9/1. Evaporation of theextract and recrystallisation from chloroform gives a further 3.9 g. (15mmol) of pure product.

M.p. 202.5°-204.5° [α]_(D) ²⁵ 22.2 (c 1; water).

elementary analysis: C₁₁ H₁₃ N₅ O₃ (263.25): calc.: C (50.19), H (4.98),N (26.60). found: C (50.39), H (5.04), N (26.69).

(c) 5-(9-Adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate

With stirring and cooling to -15°, one slowly mixes 35 ml. of 95% nitricacid (d=1.5) with 2.5 g. urea and then adds portionwise thereto a totalof 4.0 g. (15 mmol) 5-(9-adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol.One further stirs for 1 hour at -15° and slowly pours the mixture, withcooling and stirring, into 300 ml. of cold water. Subsequently, it isneutralised by the addition of 85 g. potassium hydrogen carbonate andextracted five times with 200 ml. amounts of a mixture ofchloroform/methanol 95/5. After drying over anhydrous sodium sulphate,the combined extracts are evaporated at about 50° in vacuo andrecrystallised from chloroform/petroleum ether. One obtains 3.8 g. (12.3mmol) 5-(9-adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate of m.p.158°-160° (decomp.). For analysis, one again recrystallises fromchloroform/petroleum ether.

m.p. 162°-3° (decomp.) [α]_(D) ²⁵ 80.9 (c 2; chloroform).

elementary analysis: C₁₁ H₁₂ N₆ O₅ (308.26): calc.: C (42.86), H (3.93),N (27.26). found: C (42.38), H (3.93), N (27.38).

EXAMPLE NO. 2 5-(9-Adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate(a) 5-(9-Adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-methanesulphonate

A mixture of 20.15 g. (150 mmol) adenine sodium salt, 30.2 g. (100 mmol)1.4;3.6-dianhydro-D-glucitol 2,5-dimethanesulphonate and 300 ml.dimethyl sulphoxide is heated for 24 hours, with stirring, to 100°.After cooling, one mixes with 600 ml. water, filters off with suctionthe precipitate consisting of reaction product and unreacteddimethanesulphonate and then washes twice with 50 ml. amounts of water.The precipitate is stirred with 600 ml. chloroform, whereby thedimethanesulphonate goes into solution and pure product remains behind.One obtains further product by two extractions of the chloroform phasewith 100 ml. amounts of 2 molar hydrochloric acid neutralisation of thehydrochloric acid phase with dil. aqueous sodium hydroxide solution.Subsequently, one recrystallises from ethanol and obtains 17.5 g. (51.3mmol) 5-(9-adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-methanesulphonate of m.p. 238°-240°.

[α]_(D) ²⁵ 39.8 (c 1; dimethylformamide).

Elementary analysis: C₁₂ H₁₅ N₅ O₅ S (341.34): calc.: C (42.22), H(4.43), N (20.52), S (9.39). found: C (42.36), H (4.34), N (20.76), S(9.2).

(b) 5-(9-Adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol

A solution of 30.6 g. (765 mmol) sodium hydroxide in 250 ml. water isadded, with stirring, at a rate of 10 ml./hour to a mixture, boilingunder reflux, of 87 g. (255 mmol)5-(9-adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-methanesulphonate and4 liters of water and subsequently stirs under reflux for 5 hours. Aftercooling, one neutralises the solution with 510 mmol hydrochloric acid,evaporates in vacuo, dries the residue azeotropically with n-butanol andboils it three times with 2 liter amounts of n-butanol. The butanolextracts are evaporated in vacuo and recrystallised from ethanol. Oneobtains 41.5 g. (158 mmol)5-(9-adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol of m.p. 203°. Oneobtains a further 10 g. (38 mmol) of product by evaporation of themother liquor, extraction of the residue with chloroform and evaporationof the chloroform extract.

(c) 5-(9-Adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate

With stirring and cooling to -20°, one adds portionwise a total of 15 g.urea to 200 ml. of 95% nitric acid (d=1.5). At -20°, one adds thereto,within 1 hour, 41 g. (156 mmol)5-(9-adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol in small portions andthen stirs for 1 hour at about -15°. The clear reaction mixture isslowly poured, with stirring, into 600 ml. of ice water, whereby themain amount of the reaction product crystallises out in the form of thehydrogen nitrate. The crystallisate is filtered off with suction, washedtwice with 100 ml. amounts of water, suspended in 500 ml. water,converted into the base by the addition of 2 molar aqueous sodiumhydroxide solution, again filtered off with suction and washed neutralwith water. One obtains further product by neutralisation of thefiltrate of the ice water precipitation with aqueous sodium hydroxidesolution (4.4 mol), combines with all the previously obtained filtratesand wash waters, extracts twice with 1 liter amounts of chloroform andevaporates the chloroform extracts in vacuo. The combined crude basesare dissolved in 500 ml. ethanol and, by the addition of 12 ml. of 37%hydrochloric acid (144 mmol), converted into the hydrochloride, whichcrystallises out. One filters off with suction, washes with 100 ml.ethanol, concentrates the filtrate to 150 ml. and again filters off withsuction and then washes with a little ethanol. One obtains 43.3 g. (126mmol) 5-(9-adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate ashydrochloride, with 1/2 mole of water of crystallisation.

M.p. 204°-205° decomp. [α]_(D) ²⁵ 28.6 (c 0.5; water).

Elementary analysis: C₁₁ H₁₂ N₆ O₅ xHClx1/2H₂ O (353.72): calc.: C(37.35), H (3.99), N (23.76), Cl (10.02). found: C (37.35), H (3.95), N(23.73), Cl (10.1).

The hydrogen nitrate has, after recrystallisation from methanol, them.p. 188°-190° and [α]_(D) ²⁵ 26.8 (c 0.5; water).

Elementary analysis: C₁₁ H₁₂ N₆ O₅ xHNO₃ (371.27); calc.: C (35.59), H(3.53), N (26.41). found: C (35.71), H (3.46), N (26.30).

EXAMPLE NO. 35-(6-Methylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate: (a)5-(6-Methylmercaptopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol:

A solution of 166 g. (1 mol) 6-methylmercaptopurine and 40 g. (1 mol)sodium hydroxide in 1 liter of methanol is evaporated in vacuo and driedat 140° to constant weight. One obtains 188 g. (1 mol) of the6-methylmercaptopurine 9-sodium salt. This is suspended, together with224 g. (1 mol) 1.4;3.6-dianhydro-D-glucitol 5-methanesulphonate, in 3liters dimethylformamide and heated to 130° for 24 hours, with stirringand under an atmosphere of nitrogen. Subsequently, one distils off thedimethylformamide in vacuo, takes up the residue in 2 liters of waterand continuously extracts in a rotary perforator with about 5 literschloroform. The chloroform extract is clarified over anhydrous sodiumsulphate, filtered and evaporated. The remaining oily reaction productsolidifies upon triturating with some water to give a crystalline slurrywhich is stirred with 600 ml. water, filtered off with suction andwashed 2 times with 75 ml. water. Subsequently, one dries in a vacuumdrying cabinet at 120° to constant weight and obtains 147 g. (0.5 mol)5-(6-methylmercaptopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol. Foranalysis, one recrystallises from chloroform/toluene. M.p. 146°-8°[α]_(D) ²⁵ 22.5 (c 1; chloroform).

elementary analysis: C₁₂ H₁₄ N₄ O₃ S (294.33): calc.: C (48.97), H(4.79), N (19.04), S (10.89). found: C (48.66), H (4.70), N (18.70), S(10.6).

(b) 5-(6-Methylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol

A mixture of 8.8 g. (30 mmol)5-(6-methylmercaptopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol, 8.5ml. of 33% methanolic methylamine solution (90 mmol) and 100 ml. wateris stirred at 130° for 20 hours in a closed autoclave. After cooling anddecompressing, one evaporates to dryness, dissolves the residue in 50ml. water and continuously extracts with chloroform. Evaporation of thechloroform extract, dried over anhydrous sodium sulphate, gives 7.1 g.(25.6 mmol) of oily crude product which, for purification, is convertedinto the hydrochloride and recrystallised from methanol.

M.p. 247°-250° (decomp.) [α]_(D) ²⁵ 35.9 (c 1; water).

elementary analysis: C₁₂ H₁₅ N₅ O₃ xHCl (313.74): calc.: C (45.94), H(5.14), N (22.32), Cl (11.30). found: C (46.08), H (5.25), N (22.29), Cl(11.3).

(c) 5-(6-Methylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate

To a mixture of 20 ml. glacial acetic acid, 2.5 g. (9 mmol)5-(6-methylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol and 0.6g. (10 mmol) urea one adds dropwise, with stirring and cooling to10°-15°, a solution of 1.7 ml. (40 mmol) 95% nitric acid (d=1.5) in 10ml. glacial acetic acid and subsequently 10 ml. acetic anhydride. Onestirs for 3 hours at 10°-15°, dilutes with water to a total volume of200 ml., stirs, with the addition of 5 g. sodium hydrogen carbonate, forabout 30 min., filters off with suction the reaction product obtained asa finely particulate precipitate, washes with 20 ml. water and dries.One obtains 1.4 g. (3.6 mmol)5-(6-methylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate in the form of the hydrogen nitrate. A further 0.7 g. (1.8mmol) of product is obtained by extraction of the filtrate with 3×100ml. chloroform, washing of the chloroform extract with 50 ml. water,evaporation in a vacuum and reprecipitation of the residue fromether/petroleum ether. The analytical sample is recrystallised fromwater/isopropanol. M.p. 193°-197° (decomp.)

[α]_(D) ²⁵ 28.6 (c 1; water).

Elementary analysis: C₁₂ H₁₄ N₆ O₅ xHNO₃ (385.30): calc.: C (37.40), H(3.92), N (25.45). found: C (37.34), H (3.94), N (25.21).

A part of the product is converted into the hydrochloride andrecrystallised from ethanol/isopropanol.

M.p. 201°-204° (decomp.) [α]_(D) ²⁵ 29.1 (c 1; water).

Elementary analysis: C₁₂ H₁₄ N₆ O₅ xHCl (358.74): calc.: C (40.18), H(4.21), N (23.43), Cl (9.88). found: C (40.35), H (4.24), N (23.49), Cl(9.9).

EXAMPLE NO. 45-(6-Dimethylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate (a)5-(6-Dimethylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol

A mixture of 8.8 g. (30 mmol)5-(6-methylmercaptopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol and50 ml. of 40% aqueous dimethylamine solution is stirred in a closedautoclave for 20 hours at 130°. After cooling and decompressing, oneevaporates in a vacuum and recrystallises from 20 ml. ethanol. Oneobtains 5.68 g. (19.5 mmol)5-(6-dimethylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol. Theanalytical sample is recrystallised from toluene.

M.p. 139°-141° [α]_(D) ²⁵ 29.5 (c 1; chloroform).

Elementary analysis: C₁₃ H₁₇ N₅ O₃ (291.31): calc.: C (53.60), H (5.88),N (24.04). found: C (53.90), H (5.97), N (24.11).

(b)

The esterification with nitric acid in glacial acetic acid/aceticanhydride takes place analogously to the preceding Example 3c. Oneobtains from 4.4 g. (15.1 mmol)5-(6-dimethylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol atotal of 3.35 g. (10 mmol)5-(6-dimethylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate. The analytical sample is recrystallised fromtoluene/petroleum ether. M.p. 134°-136° (decomp.) [α]_(D) ²⁵ 54.2 (c0.5; chloroform).

Elementary analysis: C₁₃ H₁₆ N₆ O₅ (336.31): calc.: C (46.43), H (4.80),N (24.99). found: C (46.38), H (4.89), N (24.69).

A part is converted into the hydrochloride and recrystallised fromisopropanol/ethanol.

M.p. 169°-170° (decomp.) [α]_(D) ²⁵ 37.5 (c 1.1; water).

Elementary analysis: C₁₃ H₁₆ N₆ O₅ xHCl (372.77).

EXAMPLE NO. 55-(6-Ethylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate(a) 5-(6-Ethylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol:

A mixture of 8.8 g. (30 mmol)5-(6-methylmercaptopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol, 8.1g. (100 mmol) ethylamine hydrochloride, 4.0 g. (100 mmol) sodiumhydroxide and 50 ml. water is stirred in a closed autoclave for 20 hoursat 130°. After cooling and decompressing, one evaporates to dryness,dissolves the residue in 100 ml. water and extracts 10 times with 100ml. amounts of chloroform. Evaporation of the chloroform extracts gives8.15 g. of oily crude product which is converted with 14 ml. 2 molarhydrochloric acid into the hydrochloride, again evaporated andrecrystallised from methanol/ether. One obtains 5.7 g. (17.4 mmol)5-(6-ethylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditolhydrochloride.

M.p. 240°-2°; [α]_(D) ²⁵ 37.7 (c 1; water).

Elementary analysis: C₁₃ H₁₇ N₅ O₃ xHCl (327.76): calc.: C (47.64), H(5.53), N (21.37), Cl (10.82). found: C (47.78), H (5.61), N (21.40), Cl(10.95).

(b)

For the esterification with nitric acid, one converts the previouslyobtained hydrochloride into the base and then treats, analogously withExample 3c, with nitric acid/glacial acetic acid/acetic anhydride. From4.4 g. (15.1 mmol) of base one obtains 2.8 g. (7 mmol)5-(6-ethylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitratein the form of the hydrogen nitrate. The analytical sample isrecrystallised from methanol. M.p. 185°-7° (decomp.);

[α]_(D) ²⁵ 31.7 (c 0.5; water).

Elementary analysis: C₁₃ H₁₆ N₆ O₅ xHNO₃ (399.33): calc.: C (39.10), H(4.29), N (24.55). found: C (39.14), H (4.37), N (24.30).

A part is converted into the hydrochloride and recrystallised fromisopropanol/ethanol.

M.p. 212°-14° (decomp.); [α]_(D) ²⁵ 48.5 (c 1; water).

Elementary analysis: C₁₃ H₁₆ N₆ O₅ xHCl (372.77): calc.: C (41.89), H(4.60), N (22.54), Cl (9.51). found: C (42.08), H (4.60), N (22.61), Cl(9.4).

EXAMPLE NO. 65-(6-Pyrrolidinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate (a)5-(6-Pyrrolidinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol

A mixture of 8.8 g. (30 mmol)5-(6-methylmercaptopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol and25 ml. (300 mmol) pyrrolidine is stirred for 20 hours in a closedautoclave at 130°. After cooling and decompressing, one distils offexcess pyrrolidine, towards the end with the addition of water, andrecrystallises the residue from water. One obtains 8.43 g. (26.6 mmol)5-(6-pyrrolidinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol.

M.p. 183.5°-185.5°; [α]_(D) ²⁵ 34.5 (c 1; chloroform).

Elementary analysis: C₁₅ H₁₉ N₅ O₃ (317.35): calc.: C (56.77), H (6.03),N (22.07). found: C (57.00), H (6.07), N (22.08).

(b) Esterification with nitric acid

To a solution of 6.35 g. (20 mmol) of the previously obtained5-(6-pyrrolidinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol in 40ml. acetic acid, one adds 1.2 g. (20 mmol) urea and adds dropwise, withstirring and cooling to about 10°-15°, a solution of 3.5 ml. (80 mmol)95% nitric acid (d=1.5) in 20 ml. glacial acetic acid and subsequentlyalso 20 ml. acetic anhydride. One further stirs for 5 hours at 15°-20°,then dilutes with water to a total volume of 270 ml., stirs for 30 min.and adds 6 g. (71 mmol) sodium hydrogen carbonate portionwise thereto.One extracts three times with 100 ml. amounts of chloroform, dries thechloroform extracts with anhydrous sodium sulphate and sodium carbonateand evaporates in a vacuum at about 40°-50°. The residue is dissolved in100 ml. ether; by the addition of petroleum ether, one precipitates outby-products as an oily precipitate. One decants off from the precipitateand adds further petroleum ether thereto, whereby the pure productslowly crystallises out. One obtains 5.53 g. (15.3 mmol)5-(6-pyrrolidinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate. The analytical sample is recrystallised fromtoluene/petroleum ether.

M.p. 146°-7°; [α]_(D) ²⁵ 58.4 (c 0.48; chloroform).

Elementary analysis: C₁₅ H₁₈ N₆ O₅ (362.35): calc.: C (49.72), H (5.01),N (23.19). found: C (49.73), H (5.08), N (23.04).

A part is converted into the hydrochloride and reprecipitated fromisopropanol/ether.

M.p. 189°-196° (decomp.); [α]_(D) ²⁵ 44.7 (c 0.53; water).

Elementary analysis: C₁₅ H₁₈ N₆ O₅ xHCl (398.81): calc.: C (45.18), H(4.80), N (21.07), Cl (8.89). found: C (45.20), H (4.83), N (21.17), Cl(9.1).

EXAMPLE NO. 75-(6-Piperidinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate(a) 5-(6-Piperidinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol

Analogously to the previous Example, 8.8 g. (30 mmol)5-(6-methylmercaptopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol arestirred together with 25 ml. (253 mmol) piperidine for 20 hours at 130°in a closed autoclave. After distilling off the excess piperidine(towards the end, with the addition of water), one triturates the oilyresidue with toluene. The now solid crude product is filtered off withsuction, dried and recrystallised from water. One obtains 7.7 g. (23.2mmol) pure5-(6-piperidinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol.

M.p. 136°-139°; [α]_(D) ²⁵ 30.1 (c 1; chloroform).

Elementary analysis: C₁₆ H₂₁ N₅ O₃ (331.38): calc.: C (57.99), H (6.39),N (21.13). found: C (58.14), H (6.48), N (21.13).

(b)

The esterification of the above-described product with nitric acid andglacial acetic acid/acetic anhydride takes place analogously to Example6b. From 5.0 g. (15 mmol) one obtains, after crystallisation fromether/petroleum ether, 2.17 g. (5.8 mmol)5-(6-piperidinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate. The analytical sample is recrystallised fromtoluene/petroluem ether.

M.p. 115°-117°; [α]_(D) ²⁵ 58.1 (c 1; chloroform).

Elementary analysis: C₁₆ H₂₀ N₆ O₅ (376.38): calc.: C (51.06), H (5.36),N (22.33). found: C (50.98), H (5.47), N (22.20).

A part of the product is converted into the hydrochloride andreprecipitated from isopropanol/ether.

M.p. 179°-184° (decomp.); [α]_(D) ²⁵ 58 (c 0.5; methanol).

Elementary analysis: C₁₆ H₂₀ N₆ O₅ xHCl (412.84): calc.: C (46.55), H(5.13), N (20.36), Cl (8.59). found: C (46.68), H (5.22), N (20.43), Cl(8.6).

EXAMPLE NO. 85-(6-Morpholinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate(a) 5-(6-Morpholinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol

Analogously to the above Examples 6a and 7a, one obtains from 8.8 g. (30mmol) 5-(6-methylmercaptopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditoland 25 ml. (287 mmol) morpholine, after stirring for 20 hours at 130° ina closed autoclave, distilling off the excess morpholine, with theaddition of water, and recrystallisation of the residue from water, 6.9g. (18.7 mmol) pure5-(6-morpholinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol in theform of the dihydrate.

M.p. 84°-88°; [α]_(D) ²⁵ 26.4 (c 1; chloroform).

Elementary analysis: C₁₅ H₁₉ N₅ O₄ x2H₂ O (369.38): calc.: C (48.78), H(6.28), N (18.96). found: C (48.71), H (6.31), N (18.74).

(b) Esterification with nitric acid

Analogously to Examples 6b and 7b, one obtains from 5.5 g. (14.5 mmol)of the above-described dihydrate, by treatment with 95% nitric acid inglacial acetic acid/acetic anhydride and recrystallisation of the crudeproduct from a little ethanol, 3.65 g. (9.6 mmol)5-(6-morpholinopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate. The analytical sample is again recrystallised fromtoluene/ether.

M.p. 173°-5°; [α]_(D) ²⁵ 53.8 (c 1; chloroform).

Elementary analysis: C₁₅ H₁₈ N₆ O₆ (378.35): calc.: C (47.62), H (4.79),N (22.21). found: C (48.16), H (4.92), N (21.72).

A part of the product is converted into the hydrochloride andreprecipitated from isopropanol/ether.

M.p. 187°-9° (decomp.); [α]_(D) ²⁵ 55.0 (c 0.51; methanol).

Elementary analysis: C₁₅ H₁₈ N₆ O₆ xHCl (414.81): calc.: C (43.43), H(4.62), N (20.26), Cl (8.55). found: C (44.20), H (4.72), N (20.25), Cl(8.1).

EXAMPLE NO. 95-[6-(4-Methylpiperazino)-purin-9-yl]-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate (a)5-[6-(4-Methylpiperazino)-purin-9-yl]-5-desoxy-1.4;3.6-dianhydro-L-iditol

Analogously to the preceding Examples, one obtains from 8.8 g. (30 mmol)5-(6-methylmercaptopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol and25 ml. (225 mmol) N-methylpiperazine, 10.2 g. (29.4 mmol) of crudeproduct. Recrystallisation from toluene gives 6.3 g. (18.2 mmol) of pureproduct.

M.p. 166°-7°; [α]_(D) ²⁵ 31.1 (c 1; chloroform).

Elementary analysis: C₁₆ H₂₂ N₆ O₃ (346.40): calc.: C (55.48), H (6.40),N (24.26). found: C (55.60), H (6.45), N (23.91).

(b)

The esterification with nitric acid is carried out analogously to thepreceding Examples. After recrystallisation from ether, one obtains5-[6-(4-methylpiperazino)-purin-9-yl]-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate.

M.p. 107°-9°; [α]_(D) ²⁵ 62.1 (c 0.53; chloroform).

Elementary analysis: C₁₆ H₂₁ N₇ O₅ (391.40): calc.: C (49.10), H (5.41),N (25.05). found: C (49.40), H (5.59), N (24.93).

A part of the product is mixed with 2 equivalents of hydrochloric acid,evaporated in a vacuum and recrystallised from ethanol/isopropanol. Oneobtains the dihydrochloride hydrate.

M.p. 173°-80° (decomp.); [α]_(D) ²⁵ 32 (c 1; water).

Elementary analysis: C₁₆ H₂₁ N₇ O₅ x2HClxH₂ O (482.34): calc.: C(39.84), H (5.22), N (20.33), Cl (14.70). found: C (40.39), H (5.39), N(20.50), Cl (14.6).

EXAMPLE NO. 105-[9-(6-N-Pivaloyl)-adenyl]-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate

A solution of 3.1 g. (10 mmol)5-(9-adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate and 7 ml. (50mmol) triethylamine in 80 ml. anhydrous dioxan is mixed, with stirringand the exclusion of moisture, with 6.1 ml. (50 mmol) pivaloyl chloride.One heats under reflux for 1 hour, allows to cool and filters off withsuction precipitated triethylamine hydrochloride. The filtrate isevaporated to a volume of about 30 ml. and stirred into 100 ml. icewater. The deposited oily precipitate is separated off and the aqueousphase extracted with 50 ml. chloroform. Precipitate and chloroformextract are combined; from the so obtained solution one precipitates outthe crude product with petroleum ether. Reprecipitation of the crudeproduct from chloroform/petroleum ether, followed by recrystallisationfrom ethanol, gives 1.83 g. (4.7 mmol)5-[9-(6-N-pivaloyl)-adenyl]-1.4;3.6-dianhydro-L-iditol 2-nitrate.

M.p. 171°-3°; [α]_(D) ²⁵ 35.8 (c 0.95; chloroform).

Elementary analysis: C₁₆ H₂₀ N₆ O₆ (392.38): calc.: C (48.98), H (5.14),N (21.42). found: C (48.96), H (5.24), N (20.61).

EXAMPLE NO. 115-[9-(6-N-Acetyl)-adenyl]-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate

The product is obtained analogously to Example No. 10 by acetylation of5-(9-adenyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate. Afterrecrystallisation from methanol/ether, it has the m.p. 158°-161° and[α]_(D) ²⁵ 35 (c 1; chlorofom).

C₁₃ H₁₄ N₆ O₆ (350.29).

EXAMPLE NO. 12 5-(7-Theophyllinyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate (a) 5-(7-Theophyllinyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol

A mixture of 44.8 g. (0.2 mol) 1.4;3.6-dianhydro-D-glucitol5-methanesulphonate, 80.8 g. (0.4 mol) theophyllin sodium salt and 600ml. dimethyl sulphoxide is stirred for 48 hours under an atmosphere ofnitrogen at 130°. One distils off the dimethyl sulphoxide in vacuo,dissolves the residue in 400 ml. hot water, after cooling extracts twicewith 200 ml. amounts of chloroform and shakes out the chloroformextracts with 200 ml. water. The combined aqueous phases are boiled upwith 30 g. active charcoal, filtered and the filtrate, afterneutralisation, evaporated to dryness. The residue is stirred with 1liter of ethanol, filtered and again evaporated. For the removal ofresidual theophyllin, one dissolves in 700 ml. 2% aqueous sodiumhydroxide solution and extracts the reaction product continuously withchloroform. The chloroform extract gives, after drying over anhydroussodium sulphate and evaporation, 27.5 g. (89 mmol)5-(7-theophyllinyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol. The analyticalsample is recrystallised from acetone/ethanol.

M.p. 196°-8°; [α]_(D) ²⁵ -27.9 (c 0.5; water).

Elementary analysis: C₁₃ H₁₆ N₄ O₅ (308.30): calc.: C (50.65), H (5.23),N (18.17). found: C (50.68), H (5.32), N (18.06).

(b) Esterification with nitric acid

To 150 ml. 95% nitric acid (d=1.5), one adds in small portions, withstirring and cooling to -15°, first 10.8 g. (180 mmol) urea andsubsequently, also in small portions, a total of 17.45 g. (56.6 mmol) ofthe above-described5-(7-theophyllinyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol. One then stirsfor 1 hour at -15°, dilutes with 850 ml. water, adds thereto a solutionof 130 g. (3.25 mol) sodium hydroxide in 1 liter water and rendersneutral by the addition of sodium hydrogen carbonate. The product isobtained as a precipitate; one filters off with suction, washes with 100ml. water and dissolves the precipitate in 1 liter chloroform. Afterdrying over anhydrous sodium sulphate, filtering and evaporating thechloroform solution, one recrystallises from acetone/methanol andobtains 14.5 g. (41 mmol)5-(7-theophyllinyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate.

M.p. 193°; [α]_(D) ²⁵ 22.9 (c 0.5; dimethylformamide).

Elementary analysis: C₁₃ H₁₅ N₅ O₇ (353.29): calc.: C (44.20), H (4.28),N (19.82). found: C (44.07), H (4.27), N (19.58).

EXAMPLE NO. 135-(6-Benzylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate (a)5-(6-Benzylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol

A mixture of 8.8 g. (30 mmol)5-(6-methylmercaptopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol and25 ml. (229 mmol) benzylamine is stirred in a closed autoclave for 20hours at 130°. After cooling and decompressing, one distils off theexcess benzylamine--towards the end, with the addition of water--invacuo, recrystallises the oily residue from acetone and obtains 6.9 g.(19.5 mmol)5-(6-benzylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol. Theanalytical sample is again recrystallised from toluene.

M.p. 151°-3°; [α]_(D) ²⁵ 28.7 (c 1; chloroform).

Elementary analysis: C₁₈ H₁₉ N₅ O₃ (353.38): calc.: C (61.18), H (5.42),N (19.82). found: C (61.17), H (5.44), N (19.82).

(b) Esterification with nitric acid

To a mixture of 5.3 g. (15 mmol) of the above-described5-(6-benzylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol, 0.9 g.(15 mmol) urea and 60 ml. acetic acid, one adds dropwise, with stirringand cooling to 10°, a solution of 2.5 ml. (60 mmol) 95% nitric acid(d=1.5) in 15 ml. acetic acid and thereafter 15 ml. acetic anhydride.One further stirs for 3 hours at 10°, adds 350 ml. of water thereto,stirs for 30 min. and then adds 5 g. sodium hydrogen carbonate thereto.The crude product is obtained as a precipitate, which is filtered offwith suction, dried and recrystallised from benzene/ether/petroleumether. One obtains 4.05 g. (about 10 mmol) of crystallisate, whichconsists of a mixture of free base and hydrogen nitrate of5-(6-benzylaminopurin-9-yl)-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate. A part thereof is dissolved in glacial acetic acid, mixedwith just about the equimolar of nitric acid, the hydrogen nitrate whichcrystallises out is filtered off with suction and recrystallised frommethanol.

M.p. 109°-110°; [α]_(D) ²⁵ 57.9 (c 0.54; chloroform).

Elementary analysis: C₁₈ H₁₈ N₆ O₅ xHNO₃ (461.40): calc.: C (46.86), H(4.15), N (21.25). found: C (46.56), H (4.20), N (21.08).

A further part is first converted into the free base, then into thehydrochloride with hydrochloric acid and recrystallised fromethanol/methanol.

M.p. 193°-201° (decomp.); [α]_(D) ²⁵ 52.7 (c 1; methanol).

Elementary analysis: C₁₈ H₁₈ N₆ O₅ xHCl (434.84): calc.: C (49.72), H(4.40), N (19.33), Cl (8.15). found: C (49.82), H (4.40), N (19.36), Cl(8.2).

EXAMPLE NO. 145-[6-(3-Phenylpropyl)-aminopurin-9-yl]-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate: (a)5-[6-(3-Phenylpropyl)-aminopurin-9-yl]-5-desoxy-1.4;3.6-dianhydro-L-iditol

A mixture of 19.1 g. (65 mmol)5-(6-methylmercaptopurin-9-yl)-5-desoxyl-1.4;3.6-dianhydro-L-iditol and94 ml. (650 mmol) 3-phenylpropylamine is heated in a closed steelautoclave for 36 hours at 150°. After cooling and decompressing, oneadds thereto 80 ml. acetic acid and 500 ml. water and extracts twicewith 300 ml. amounts of chloroform. The chloroform extracts are washedwith 300 ml. water and extracted twice with a solution of 25 ml. 37%hydrochloric acid in 200 ml. water. The hydrochloric acid extracts arerendered alkaline with aqueous sodium hydroxide solution and extractedwith 400 ml. dichloromethane. The dichloromethane extract gives, afterdrying over anhydrous sodium sulphate, filtering and evaporating, 20 g.(52.4 mmol) of crude base which is dissolved, with warming, in 150 ml.isopropanol and mixed with 15 ml. 37% hydrochloric acid (180 mmol). Uponcooling, 18.8 g. (41.4 mmol) of pure product crystallise out in the formof the dihydrochloride.

M.p. 159°-62°; [α]_(D) ²⁵ 30.6 (c 0.4; water).

Elementary analysis: C₂₀ H₂₃ N₅ O₃ x2 HCl(454.36): calc.: C (52.86), H(5.55), N (15.41), Cl (15.61). found: C (53.23), H (5.55), N (15.41), Cl(14.4).

(b) Esterification with nitric acid

To a mixture of 11.4 g. (30 mmol)5-[6-(3-phenylpropyl)-aminopurin-9-yl]-5-desoxy-1.4;3.6-dianhydro-L-iditol(obtained from the previously described dihydrochloride), 1.8 g. (30mmol) urea and 120 ml. glacial acetic acid, one adds dropwise, withstirring and cooling to 10°-15°, a solution of 5.2 ml. (120 mmol) 96%nitric acid (d=1.5) in 30 ml. glacial acetic acid and subsequently 30ml. acetic anhydride, then stirs for 8 hrs. at 15°-20°, dilutes with 800ml. water and leaves to stand overnight. After the addition of 75 ml. 2molar aqueous sodium hydroxide solution, one stirs up thoroughly,extracts 2 times with 500 ml. amounts of chloroform, washes the combinedchloroform extracts free of acid with dilute aqueous sodium hydroxidesolution, dries over anhydrous sodium sulphate, filters and evaporatesunder reduced pressure. One obtains 11.8 g. (about 25 mmol) of crudeproduct which is contaminated by product nitrated on the phenyl radical.For purification, one converts into the hydrochloride in ethanolicsolution with 27 mmol hydrochloric acid, again evaporates, extracts theby-products at boiling temperature with chloroform and recrystallisesthe insoluble main product from ethanol/chloroform and from ethanol. Theso obtained5-[6-(3-phenylpropyl)-aminopurin-9-yl]-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate hydrochloride has the m.p. 200°-203° (decomp.); [α]_(D) ²⁵41.2 (c 0.21; dimethylformamide).

Yield: 4.84 g. (10.5 mmol).

Elementary analysis: C₂₀ H₂₂ N₆ O₅ xHCl (462.89): calc.: C (51.90), H(5.01), N (18.16), Cl (7.66). found: C (52.00), H (5.07), N (18.26), Cl(8.0).

EXAMPLE NO. 15 2-(9-Adenyl)-2-desoxy-1.4;3.6-dianhydro-D-glucitol5-nitrate (a) 1.4;3.6-Dianhydro-D-mannitol 2-methanesulphonate

To a solution of 877 g. (6 mol) 1.4;3.6-dianhydro-D-mannitol in 6 litersof pyridine, one adds dropwise, with stirring and exclusion of moisture,as well as cooling to -15°, within 6 hrs., 525 ml. (6.6 mol)methanesulphonyl chloride, further stirs for 3 days at -15° and thendistils off the pyridine under reduced pressure. Upon mixing the oilyresidue with 2.7 liters of water, pure 1.4;3.6-dianhydro-D-mannitol2,5-dimethanesulphonate crystallises out, which is separated off andwashed 2 times with 700 ml. amounts of water. The combined filtrates aremixed with a solution of 264 g. (6.6 mol) sodium hydroxide in 2.5 litersof water, adjusted to pH=7 by the addition of sodium hydrogen carbonate,evaporated under reduced pressure and dried azeotropically withchloroform. The residue is hot extracted twice with 2.5 liter amounts ofchloroform and filtered. The combined chloroform extracts are extracted5 times with 1 liter amounts of water. Upon concentration of the aqueousphases, the 1.4;3.6-dianhydro-D-mannitol 2-methanesulphonatecrystallises out. The mother liquor remaining after the suctionfiltration gives further product after evaporation and recrystallisationfrom ethanol. Residual product is obtained by evaporation of theethanolic mother liquor, dissolving of the residue in water andcontinuous extraction of the aqueous solution with chloroform in arotary percolator. Unreacted 1.4;3.6-dianhydro-D-mannitol remains in theaqueous phase. In all, one obtains 369 g. (1.77 mol)1.4;3.6-dianhydro-D-mannitol 2-methanesulphonate (besides 465 g.=1.54mol of the dimethanesulphonate). The analytical sample has, afterrecrystallisation from chloroform, the m.p. 111°-112° and [α]_(D) ²⁵ 118(c 1.0; acetone).

Elementary analysis: C₇ H₁₂ O₆ S (224.24). calc.: C (37.50), H (5.40), S(14.30). found: C (37.41), H (5.59), S (13.7).

(b) 2-(9-Adenyl)-2-desoxy-1.4;3.6-dianhydro-D-glucitol

A mixture of 112 g. (0.5 mol) 1.4;3.6-dianhydro-D-mannitol2-methanesulphonate, 86 g. (0.55 mol) adenine sodium salt and 1500 ml.anhydrous dimethyl sulphoxide is stirred for 1 day at 100°. One distilsoff the solvent under reduced pressure as far as possible, mixes theresidue with 4.5 liters of water and extracts continuously withchloroform for 2 days in a 5 l. rotary perforator (Normag). The crudeproduct crystallises out from the chloroform phase which, afterrecrystallisation from ethanol/water, gives 6.9 g. (26.2 mmol) of pureproduct. The filtrate is combined with the aqueous phase of thepercolation and concentrated to about 100 ml. A further 21.3 g. (80.9mmol) of product crystallise out.

Total yield: 28.2 g. (107 mmol).

M.p. (ethanol/water): 265°-7°;

[α]_(D) ²⁵ 20.8 (c 1.0; water).

Elementary analysis: C₁₁ H₁₃ N₅ O₃ (263.25): calc.: C (50.19), H (4.98),N (26.20). found: C (49.97), H (5.04), N (26.80).

About 40% of unreacted 1.4;3.6-dianhydro-D-mannitol 2-methanesulphonatecan be recovered from the chloroform phase of the perforation.

(c) 2-(9-Adenyl)-2-desoxyl-1.4;3.6-dianhydro-D-glucitol 5-nitrate

With stirring and cooling to -20°, one adds a solution of 4 g. (67 mmol)urea in 170 ml. conc. sulphuric acid (d=1.84; about 3 mol) dropwise to60 ml. of 96% nitric acid (d=1.5; 1.37 mol) and subsequently a solutionof 21 g. (80 mmol) 2-(9-adenyl)-2-desoxy-1.4;3.6-dianhydro-D-glucitol in12 ml. water +30 ml. methanesulphonic acid and then stirs at -20° forone hour. One pours the mixture into 1 liter of ice water and addsdropwise thereto, with stirring, a solution of 300 g. (7.5 mol) sodiumhydroxide in 1 liter of water. By the addition of aqueous sodiumhydrogen carbonate, one completes the neutralisation and extracts themixture 4 times with 1.5 liter amounts of chloroform. The combinedchloroform phases give, after drying over anhydrous sodium sulphate,filtering and evaporating reduced pressure, 16.8 g. (54.5 mmol) of crudebase. This is converted into the hydrochloride and gives, afterrecrystallisation from methanol, 16.3 g. (47.3 mmol)2-(9-adenyl)-2-desoxy-1.4;3.6-dianhydro-D-glucitol 5-nitratehydrochloride.

M.p. (from water): 214°-5° (decomp.); [α]_(D) ²⁵ 62.6 (c 0.5; water).

Elementary analysis: C₁₁ H₁₂ N₆ O₅ xHCl (344.71): calc.: C (38.33), H(3.80), N (24.38), Cl (10.28). found: C (38.21), H (3.59), N (24.46), Cl(10.3).

EXAMPLE NO. 165-{6-[3-(4-Chlorophenyl)-propylamino]-purin-9-yl}-5-desoxyl-1.4;3.6-dianhydro-L-iditol2-nitrate (a)5-{6-[3-(4-Chlorophenyl)-propylamino]-purin-9-yl}-5-desoxy-1.4;3.6-dianhydro-L-iditol

Preparation analogous to Example 14 a by the reaction of3-(4-chlorophenyl)-1-aminopropane with5-(6-methylmercaptopurin-9-yl)-5-desoxyl-1.4;3.6-dianhydro-L-iditol.After conversion into the hydrochloride and recrystallisation from 96%ethanol, one obtains, in 80% yield, the pure product in the form of thehydrochloride hemihydrate with m.p. 116°-120° and [α]_(D) ²⁵ 39 (c 0.4;ethanol).

Elementary analysis: C₂₀ H₂₂ ClN₅ O₃ xHClx0.5 H₂ O (461.35): calc.: C(52.07), H (5.24), N (15.18), Cl (15.37). found: C (52.34), H (5.20), N(15.15), Cl (15.5).

(b) Esterification with nitric acid

Analogously to Example 14 b. After conversion into the hydrochloride andrecrystallisation twice from methanol/water, one obtains, in 24% yield,pure5-{6-[3-(4-chlorphenyl)-propylamino]-purin-9-yl}-5-desoxy-1.4;3.6-dianhydro-L-iditol2-nitrate hydrochloride with the m.p. 183°-185° (decomp.) and [α]_(D) ²⁵42.5 (c 0.2; ethanol).

Elementary analysis: C₂₀ H₂₁ ClN₆ O₅ xHCl (497.35): calc.: C (48.30), H(4.46), N (16.90), Cl (14.26). found: C (48.38), H (4.46), N (16.72), Cl(14.1).

In the investigation of the pharmacological properties of the compoundsaccording to the invention, as comparison compounds thee were alwaysused the commercially available compounds isosorbide dinitrate (ISDN)and isosorbide mononitrate (ISMN), whereby, in the case of ISMN, it is1.4;3.6-dianhydro-D-glucitol 2-nitrate.

The coronary flowthrough-increasing effectiveness of the compoundsaccording to the invention was determined on isolated guinea pig hearts(isolated hearts according to Langendorff, Method according to Bunger etal.; Pfluger's Archiv. 353, 317-325 (1975)). After reaching thestationary state in the 30th minute, the hearts were infused in eachcase with 50 ml. of tyrode solution with a content of test substance of,in each case, 25 μg./ml. Each test substance was tested on 3-6 hearts.

In each case, there were measured the inotropism, the throughflow andthe frequency, whereby the values given in Table I are average values ofthe percentage change in comparison with the initial values. Thecomparison of the measured values shows that the coronaryflowthrough-increasing effectiveness of the compounds according to theinvention is greater than that of ISMN; the coronaryflowthrough-increasing effectiveness of some compounds even exceeds thatof ISDN.

                  TABLE I                                                         ______________________________________                                        Experiments on Langendorff hearts                                             Substance                                                                     compound                                                                      according                                                                             dose     Inotro-  Flow-  Fre-                                         to Example                                                                            (μg/ml)                                                                             pism     through                                                                              quency                                                                              Remarks                                ______________________________________                                        1c or 2c                                                                              25       -8.97    +92.13 +4.92                                        3c      25       -4.74    +39.88 +0.60                                        4b      25       -7.49    +103.37                                                                              -4.92                                        5b      25       -6.10    +66.97 -1.54                                        6b      25       -12.96   +23.94 +0.15                                        9b      25       -5.15    +35.93 -7.58                                        12b     25       0        +11.43 +7.84                                        ISDN    25       -8.11    +91.54 +2.00 comparison                             ISMN    25       -2.67     +9.11 -0.51 compounds                              ______________________________________                                    

The spasmolytic effectiveness of the compounds according to theinvention was determined on isolated rat aorta preparations withnoradrenaline-induced and potassium chloride-induced contractions(method according to Wende and Peiper, Pfluger's Archiv, 320, 133-141(1970); and Towart and Stoepel, Naunyn-Schmiedeberg's Archives ofPharmacology; Suppl. Vol., 308, R 18 (1979)).

In Table II are given the concentrations of the test substances whichare necessary for a 50% inhibition of the spasm (ED₅₀ values). Thespasmolytic effectivenesses of the compounds according to the inventionare quite preponderantly better than those of ISMN and ISDN, especiallywhen one takes into account the pharmacologically important relationshipof the effective doses in the case of noradrenaline spasm and potassiumchloride spasm.

                  TABLE II                                                        ______________________________________                                        ED.sub.50 values for spasmolytic actions                                      Substance                                                                     compound                   Potassium chloride                                 according   Noradrenaline spasm                                                                          spasm                                              to Example  (Mol/l.)       (Mol/l.)                                           ______________________________________                                        1c or 2c    1.35 × 10.sup.-7                                                                       2.80 × 10.sup.-6                             3c          4.80 × 10.sup.-7                                                                       4.60 × 10.sup.-6                             4b          2.20 × 10.sup.-7                                                                       2.90 × 10.sup.-5                             5b          3.80 × 10.sup.-7                                                                       1.30 × 10.sup.-5                             6b          5.40 × 10.sup.-7                                                                       4.07 × 10.sup.-6                             7b          2.40 × 10.sup.-7                                                                       2.90 × 10.sup.-6                             8b          2.90 × 10.sup.-7                                                                       3.00 × 10.sup.-6                             9b          2.65 × 10.sup.-6                                                                       2.50 × 10.sup.-5                             10          3.02 × 10.sup.-7                                                                       6.50 × 10.sup.-6                             12b         3.20 × 10.sup.-6                                                                       4.20 × 10.sup.-6                             13b         1.68 × 10.sup.-8                                                                       2.40 × 10.sup.-6                             ISDN (comparison)                                                                         1.30 × 10.sup.-6                                                                       3.10 × 10.sup.-6                             ISMN (comparison)                                                                         1.60 ×  10.sup.-5                                                                      2.40 × 10.sup.-6                             ______________________________________                                    

The blood pressure-lowering effectiveness of the compounds according tothe invention on narcotised guinea pigs after intravenous administrationwas measured. The values given in Table III show that the compoundsaccording to the invention are substantially more effective than ISMN,whereby the adenyl derivative of 1.4;3.6-dianhydro-iditol mononitrate(compound according to Example 1c/2c) is even more effective than ISDN.

The heart-circulation effectiveness of the compounds according to theinvention was determined on mongrel cats of 2.5 to 3.5 kg. body weightby intraduodenal administration. The animals were narcotised with amixture of chloroalose-urethane (1.2 g./kg. urethane +40 mg./kg.chloralose administered i.p.). They breathed spontaneously through atracheal canula. The A. carotis sinistra was used in order to place acatheter tip monometer in the left chamber of the heart. The V.jugularis served for injection purposes. Via the A. femoralis dextra, acatheter was inserted up into the Aorta descendans and connected to apressure recorder (Statham P 23Db). The heart frequency was recordedwith a pulse frequency measurer (Firm Hugo Sachs Elektronik) from theleft ventricular pressure signal. A duodenal loop was exposed bylaparotomy. The substances to be tested were injected directly into thelumen. As follows from the values given in Table IV, the degree of bloodpressure lowering in the case of the compounds according to theinvention is significantly higher and, in particular, longer lastingthan in the case of the comparison compounds ISMN and ISDN. This meansthat the compounds according to the invention are gentle on the heartand possess a lesser negative inotropic action than the comparisoncompounds.

The circulatory-pharmacological effectiveness of the compounds accordingto the invention was determined on the narcotised dog with intravenousadministration. The investigations were carried out on mongrel dogs ofboth sexes, body weight 20.5 to 29 kg. After a twelve hour fastingperiod, the animals received 2 mg./kg. morphine s.c. on the morning ofthe test day. About 30 minutes thereafter, narcosis was induced with 25mg./kg. nembutal i.v. and maintained by continuous infusion with 5mg./kg./h. The animals were aerated constantly through a tracheal tubewith an N₂ O/O₂ mixture (2:1). The CO₂ of the expired air was measuredcontinuously, the pH value of the blood about every 20 minutes.

For the continuous measurement of the arterial blood pressure, theArteria saphena dextra was exposed, the Arteria femoralis sinistra forthe application of a Statham flow measurement head. From the Arteriabrachialis sinistra, a thermoprobe was pushed into the aortal arch; itserved for the measurement of the heart minute volume by means of thethermodilution method. With X-ray monitoring, a catheter tip manometerwas introduced through the Arteria carotis dextra into the leftventricle and the left ventricular end diastolic pressure determinedwith it. From the right Vena jugularis, a double-lumen catheter wasintroduced into the Arteria pulmonalis; via one lumen, an ice-cooledisotonic NaCl solution was injected for the determination of the heartminute volume, via the other the blood pressure in the Arteriapulmonalia was measured. Through one vein of the left front paw, acatheter was pushed into the right atrium for pressure measurement. Witha differentiator, from the pressure in the left ventricle there wascalculated the rate of pressure increase ("dp/dt") as a measure of thecontractability. After completion of the preparation, the animals wereanti-coagulated with 500 IU/kg. heparin.

After a stabilisation period of about 30 minutes, the heart minutevolume was determined. Groups of four animals then each received 1mg./kg. ISDN or of 1c/2c administered i.v. The parameters of heartfrequency, arterial blood pressure, pulmonalis pressure, pressure in theright atrium, left ventricular pressure, dp/dt and average femoralisflow were continuously recorded with a Beckmann 8-channel recorder.Further measurements took place after the 2nd, 5th, 7th, 10th, 20th,25th, 30th, 40th, 50th, 60th, 120th, 150th and 180th minute. All flowvalues and values derived therefrom were referred to a body weight of 20kg. Heart capacities and resistances were calculated in the usualmanner.

As follows from the values given in Tables V (circulatorypharmacological effects of the comparison compound ISDN) and VI(circulatory pharmacological effects of the compound 1c/2c according tothe invention), the effectiveness of the compound according to theinvention is better than that of the comparison compound ISDN,especially with regard to the lowering of the end diastolic pressure inthe left ventricle and the long-term lowering of the pressure in the A.pulmonalis.

LEGENDS TO TABLES V AND VI

Circulatory pharmacological effects of ISDN (Tab. V) and 1c/2c (Tab. VI)on the dog after intravenous administration (1 mg./kg.). Average valuesand standard errors from groups of 4 animals before the administration(v) or at various times (in min.) after the administration. HF: heartfrequency (min⁻¹); AP_(syst)., AP_(diast). : systolic and diastolicaorta pressure (mm.Hg); PRA:pressure in the right atrium (mm.Hg); PAP:average pressure in the A. pulmonalis (mm.Hg); LVEDP: end diastolicpressure in the left ventricle (mm.Hg); dp/dt: rate of pressure increasein the left ventricle (mm.Hg/sec.); HL_(L) : heart capacity left,referred to 20 kg. body weight (W); HL_(R) : heart capacity right,referred to 20 kg. body weight (mW); SV: beat volume, referred to 20 kg.body weight (ml.); BF_(Fem) : blood flow in the A. femoralis, referredto 20 kg. body weight (ml./min.); W_(Fem) : femoralis resistance,referred to 20 kg. body weight (KU); HZV: heart minute volume, referredto 20 kg. body weight (1/min.); W_(AP) : pulmonalis resistance, referredto 20 kg. body weight (U); W_(TP) : total peripheral resistance,referred to 20 kg. body weight (U).

                  TABLE III                                                       ______________________________________                                        Blood pressure experiments on guinea pigs                                               blood pressure                                                             dose     previously  afterwards                                                                              Δ                                 substance                                                                            mg/kg    mm. Hg      mm. Hg    mm. Hg                                  ______________________________________                                        ISDN   0.25     68.70 ± 2.30                                                                           57.00 ± 2.10                                                                         -11.70                                         1.00     66.00 ± 3.50                                                                           46.30 ± 0.90                                                                         -19.70                                         2.50     66.70 ± 1.70                                                                           37.70 ± 0.90                                                                         -29.00                                  ISMN   0.25     57.60 ± 3.10                                                                           53.90 ± 3.10                                                                          -3.70                                         1.00     54.70 ± 3.80                                                                           48.40 ± 3.20                                                                          -6.30                                         2.50     52.30 ± 4.80                                                                           41.40 ± 3.90                                                                         -10.90                                  1c/2c  0.25     68.25 ± 2.50                                                                           50.50 ± 2.33                                                                         -17.75                                         1.00     69.50 ± 2.90                                                                           41.50 ± 3.97                                                                         -28.00                                         2.50     70.00 ± 2.27                                                                           38.75 ± 2.66                                                                         -31.25                                  3c     0.25     79.50 ± 2.50                                                                           79.25 ± 2.56                                                                          -0.25                                         1.00     79.50 ± 2.66                                                                           71.50 ± 3.97                                                                          -8.00                                         2.50     77.00 ± 2.80                                                                           61.50 ± 3.23                                                                         -15.50                                  4b     0.25     73.75 ± 2.14                                                                           63.25 ± 4.23                                                                         -10.50                                         1.00     74.00 ± 1.91                                                                           59.00 ± 1.47                                                                         -15.00                                         2.50     72.00 ± 2.45                                                                           43.50 ± 2.50                                                                         -28.50                                  5b     0.25     76.50 ± 2.66                                                                           71.00 ± 5.04                                                                          -5.50                                         1.00     78.50 ± 1.70                                                                           65.75 ± 3.75                                                                         -12.75                                         2.50     76.25 ± 2.59                                                                           51.00 ± 3.13                                                                         -25.25                                  6b     0.25     65.00 ± 4.02                                                                           51.50 ± 4.94                                                                         -13.50                                         1.00     65.50 ± 2.36                                                                           44.75 ± 2.84                                                                         -20.75                                         2.50     62.00 ± 2.04                                                                           37.25 ± 1.11                                                                         -24.75                                  9b     0.25     72.50 ± 6.20                                                                           70.25 ± 8.39                                                                          -2.25                                         1.00     73.25 ± 6.24                                                                           69.75 ± 7.44                                                                          -3.50                                         2.50     72.50 ± 5.24                                                                           59.75 ± 4.82                                                                         -12.75                                  ______________________________________                                    

                                      TABLE IV                                    __________________________________________________________________________    substance                                                                          time (min.)                                                                          frequency                                                                           blood pressure                                                                           dp/dt                                            + dose                                                                             after admin.                                                                         min.sup.-1                                                                          mm. Hg Δ                                                                           mm sec Δ                                   __________________________________________________________________________    ISDN  0     174.3 ± 9.3                                                                      104.3 ± 7.7                                                                       -13.9                                                                             8800 ± 831                                                                        -800                                      5 mg/kg                                                                            10     179.3 ± 7.7                                                                       90.4 ± 12.5                                                                      -13.1                                                                              8000 ± 1097                                                                      -1133                                          30     177.7 ± 7.7                                                                       91.2 ± 10.0                                                                      -10.1                                                                             7667 ± 807                                                                        -1167                                          60     175.0 ± 8.6                                                                       94.2 ± 9.2                                                                        -9.3                                                                             7633 ± 743                                                                        -1750                                          120    166.7 ± 9.4                                                                       95.0 ± 9.6                                                                           7050 ± 661                                    1c/2c                                                                               0     171.6 ± 6.2                                                                      124.2 ± 8.3                                                                       -15.6                                                                             7220 ± 611                                                                        +280                                      5 mg/kg                                                                            10     180.4 ± 4.3                                                                      108.6 ± 8.5                                                                       -16.4                                                                             7500 ± 522                                                                        -260                                           30     177.2 ± 5.4                                                                      107.8 ± 8.4                                                                       -17.6                                                                             6960 ±  564                                                                       -120                                           60     177.6 ± 5.1                                                                      106.6 ± 7.8                                                                       -18.0                                                                             7100 ± 721                                                                        -220                                           120    178.8 ± 4.4                                                                      106.2 ± 5.6                                                                            7000 ± 1026                                  __________________________________________________________________________     Legend:                                                                       Heart frequency, blood pressure and inotropism at different times after       intraduodenal administration of ISDN or substance 1c/2c to cats.              Average values + standard errors from groups of 6 animals.               

                                      TABLE V                                     __________________________________________________________________________    (comparison): ISDN                                                            __________________________________________________________________________         v   2   5   7   10  15  20  25                                           __________________________________________________________________________    HF   109.5                                                                             143.7                                                                              133.5                                                                             128.7                                                                             121.7                                                                            118.2                                                                             112.5                                                                             112.0                                             ±7.1                                                                           ±5.1                                                                           ±11.9                                                                          ±11.1                                                                          ±10.6                                                                          ±9.8                                                                           ±8.8                                                                           ±8.5                                      AP.sub.syst                                                                        166.9                                                                             145.7                                                                             152.9                                                                             152.9                                                                             152.9                                                                             154.8                                                                             154.8                                                                             156.6                                             ±4.9                                                                           ±7.9                                                                           ±6.4                                                                           ±6.5                                                                           ±5.6                                                                           ±4.7                                                                           ±5.6                                                                           ±4.7                                      AP.sub.diast                                                                        95.6                                                                              99.4                                                                             102.2                                                                             100.3                                                                              98.4                                                                              98.4                                                                              96.6                                                                              98.4                                             ±10.8                                                                          ±9.7                                                                           ±7.7                                                                           ±8.0                                                                           ±9.0                                                                           ±9.0                                                                           ±7.4                                                                           ±7.2                                      PRA   2.06                                                                              1.12                                                                              1.72                                                                              1.78                                                                              1.87                                                                              1.97                                                                              2.15                                                                              2.38                                             ±0.5                                                                           ±0.6                                                                           ±0.7                                                                           ±0.7                                                                           ±0.6                                                                           ±0.7                                                                           ±0.7                                                                           ±0.8                                       ##STR10##                                                                          14.3 ±1.2                                                                      11.1 ±0.7                                                                      11.5 ±0.8                                                                      12.6 ±1.4                                                                      12.6 ±1.4                                                                      12.7 ±1.6                                                                      12.6 ±1.3                                                                       13.3 ±1.5                               LVEDP                                                                               7.69                                                                              4.97                                                                              5.81                                                                              6.0                                                                               6.28                                                                              6.47                                                                              6.75                                                                              7.03                                             ±1.3                                                                           ±1.1                                                                           ±0.8                                                                           ±0.9                                                                           ±0.8                                                                           ±0.7                                                                           ±0.7                                                                           ±0.7                                      dp/dt                                                                               2268.7                                                                            2868.7                                                                           2606.2                                                                             2587.5                                                                            2550.0                                                                            2512.5                                                                            2418.7                                                                            2456.2                                           ±271.1                                                                         ±370.4                                                                         ±30.1                                                                          ±291.0                                                                         ±302.2                                                                         ±288.0                                                                         ±281.0                                                                         ±295.9                                    HL.sub.L                                                                            0.76                                                                              0.94                                                                              0.95                                                                              0.85                                                                              0.84                                                                              0.79                                                                              0.78                                                                              0.76                                             ±0.13                                                                          ±0.15                                                                          ±0.17                                                                          ±0.14                                                                          ±0.15                                                                          ±0.14                                                                          ±0.13                                                                          ±0.13                                     HL.sub.R                                                                            85.1                                                                              85.3                                                                              81.4                                                                              83.0                                                                              82.4                                                                              78.9                                                                              75.3                                                                              76.3                                             ±19.8                                                                          ±11.3                                                                          ±13.9                                                                          ±18.3                                                                          ±17.9                                                                          ±21.3                                                                          ±16.3                                                                          ±18.2                                     SV    27.7                                                                              26.3                                                                              27.4                                                                              25.9                                                                              27.4                                                                              26.8                                                                              27.9                                                                              26.8                                             ±2.8                                                                           ±1.8                                                                           ±2.1                                                                           ±1.5                                                                           ±1.9                                                                           ±2.3                                                                           ±2.3                                                                           ±2.1                                      BF.sub.Fem                                                                          44.9                                                                              31.2                                                                              35.4                                                                              37.3                                                                              38.4                                                                              40.9                                                                              40.9                                                                              41.9                                             ±11.7                                                                          ±6.5                                                                           ± 7.7                                                                          ±7.1                                                                           ±6.6                                                                           ±8.6                                                                           ±7.2                                                                           ±8.2                                      W.sub.Fem                                                                           0.39                                                                              0.55                                                                              0.49                                                                              0.45                                                                              0.42                                                                              0.41                                                                              0.40                                                                              0.40                                             ±0.1                                                                           ±0.1                                                                           ±0.1                                                                           ±0.1                                                                           ±0.05                                                                          ±0.1                                                                           ±0.05                                                                          ±0.1                                      HZV   3.03                                                                              3.8                                                                               3.7                                                                               3.3                                                                               3.4                                                                               3.2                                                                               3.1                                                                               3.0                                              ±0.4                                                                           ±0.4                                                                           ±0.5                                                                           ±0.4                                                                           ±0.4                                                                           ±0.4                                                                           ±0.4                                                                           ±0.4                                      W.sub.AP                                                                            0.31                                                                              0.23                                                                              0.22                                                                              0.27                                                                              0.26                                                                              0.26                                                                              0.25                                                                              0.27                                             ±0.05                                                                          ±0.05                                                                          ±0.04                                                                          ±0.03                                                                          ±0.03                                                                          ±0.03                                                                          ±0.02                                                                          ±0.02                                     W.sub.TP                                                                            5.27                                                                              4.02                                                                              4.39                                                                              4.72                                                                              4.66                                                                              4.96                                                                              4.92                                                                              5.22                                             ±0.4                                                                           ±0.1                                                                           ±0.4                                                                           ±0.3                                                                           ±0.3                                                                           ±0.3                                                                           ±0.3                                                                           ±0.4                                      __________________________________________________________________________         30  40  50  60  90  120 150 180                                          __________________________________________________________________________    HE    110.0                                                                            108.0                                                                              109.2                                                                             107.5                                                                            109.5                                                                             104.2                                                                             103.7                                                                             103.7                                             ±17.5                                                                          ±9.8                                                                           ±21.2                                                                          ±10.1                                                                          ±9.9                                                                           ±7.7                                                                           ±6.9                                                                           ±5.9                                      AP.sub.syst                                                                        155.6                                                                             158.4                                                                             157.5                                                                             159.4                                                                             163.2                                                                             161.2                                                                             161.2                                                                             161.2                                             ±3.2                                                                           ±4.9                                                                           ±5.1                                                                           ±5.8                                                                           ±5.8                                                                           ±6.6                                                                           ±4.7                                                                           ±4.8                                      AP.sub.diast                                                                        98.1                                                                             101.2                                                                             101.2                                                                             101.2                                                                              99.4                                                                              97.5                                                                              95.6                                                                              95.6                                             ±5.9                                                                           ±6.5                                                                           ±6.5                                                                           ±6.5                                                                           ±5.6                                                                           ±5.5                                                                           ±4.5                                                                           ±5.6                                      PRA   2.34                                                                              2.34                                                                              2.29                                                                              2.53                                                                              2.53                                                                              2.81                                                                              3.0                                                                               2.81                                             ±0.7                                                                           ±0.7                                                                           ±0.6                                                                           ±0.7                                                                           ±0.7                                                                           ±0.8                                                                           ±0.9                                                                           ±0.8                                       ##STR11##                                                                          13.5 ±1.5                                                                      14.0 ±1.5                                                                      14.0 ±1.6                                                                      14.1 ±1.6                                                                      14.6 ±1.8                                                                      15.0 ±2.0                                                                      14.6 ±1.5                                                                      15.5 ±1.6                                LVEDP                                                                               7.22                                                                              7.60                                                                              7.60                                                                              7.77                                                                              7.98                                                                              8.34                                                                              7.78                                                                              7.60                                             ±0.6                                                                           ±0.7                                                                           ±0.7                                                                           ±0.7                                                                           ±0.9                                                                           ±1.0                                                                           ±1.0                                                                           ±1.2                                      dp/dt                                                                               2390.6                                                                            2343.7                                                                            2306.2                                                                            2250.0                                                                            2231.2                                                                            2118.7                                                                            2025.0                                                                            2043.7                                           ±284.9                                                                         ±281.2                                                                         ±269.2                                                                         ±250.6                                                                         ± 251.2                                                                        ±221.5                                                                         ±181.1                                                                         ±206.2                                    HL.sub.L                                                                            0.76                                                                              0.76                                                                              0.77                                                                              0.78                                                                              0.77                                                                              0.72                                                                              0.74                                                                              0.79                                             ±0.10                                                                          ±0.13                                                                          ±0.13                                                                          ±0.14                                                                          ±0.12                                                                          ±0.10                                                                          ±0.10                                                                          ±0.12                                     HL.sub.R                                                                            78.6                                                                              80.5                                                                              81.1                                                                              81.9                                                                              85.4                                                                              81.5                                                                              79.7                                                                              92.4                                             ±16.5                                                                          ±17.2                                                                          ±18.6                                                                          ±20.1                                                                          ±20.5                                                                          ±18.9                                                                          ±17.2                                                                          ±18.7                                     SV    27.8                                                                              27.7                                                                              27.4                                                                              28.2                                                                              27.7                                                                              28.1                                                                              28.6                                                                              30.6                                             ±2.1                                                                           ±1.9                                                                           ±1.6                                                                           ±1.6                                                                           ±1.9                                                                           ±1.8                                                                           ±1.6                                                                           ±1.9                                      BF.sub.Fem                                                                          41.5                                                                              42.9                                                                              43.9                                                                              42.3                                                                              44.4                                                                              49.3                                                                              51.3                                                                              53.7                                             ±8.1                                                                           ±8.2                                                                           ±9.2                                                                           ±8.9                                                                           ±8.2                                                                           ±7.7                                                                           ±9.8                                                                           ±10.8                                     W.sub.Fem                                                                           0.40                                                                              0.40                                                                              0.39                                                                              0.41                                                                              0.38                                                                              0.33                                                                              0.32                                                                              0.32                                             ±0.1                                                                           ±0.05                                                                          ±0.1                                                                           ±0.1                                                                           ±0.04                                                                          ±0.03                                                                          ±0.05                                                                          ±0.06                                     HZV   3.0                                                                               3.0                                                                               3.0                                                                               3.0                                                                               3.0                                                                               2.9                                                                               3.0                                                                               3.2                                              ± 0.3                                                                          ±0.3                                                                           ±0.4                                                                           ±0.4                                                                           ±0.4                                                                           ±0.2                                                                           ±0.3                                                                           ±0.3                                      W.sub.AP                                                                            0.27                                                                              0.28                                                                              0.27                                                                              0.26                                                                              0.27                                                                              0.28                                                                              0.29                                                                              0.31                                             ±0.03                                                                          ±0.04                                                                          ±0.04                                                                          ±0.03                                                                          ±0.06                                                                          ±0.08                                                                          ±0.05                                                                          ±0.05                                     W.sub.TP                                                                            5.13                                                                              5.41                                                                              5.38                                                                              5.32                                                                              5.35                                                                              5.36                                                                              5.22                                                                              4.89                                             ±0.4                                                                           ±0.5                                                                           ±0.5                                                                           ±0.5                                                                           ±0.6                                                                           ±0.3                                                                           ±0.3                                                                           ±0.3                                      __________________________________________________________________________

                                      TABLE VI                                    __________________________________________________________________________    Compound acc. to Example 1c/2c                                                __________________________________________________________________________         v   2   5   7   10  15  20  25                                           __________________________________________________________________________    HF    97.5                                                                              158.7                                                                             148.7                                                                             146.7                                                                             141.2                                                                             133.0                                                                             129.7                                                                             125.7                                            ±13.0                                                                          ±20.7                                                                          ±22.1                                                                          ±22.5                                                                          ±22.5                                                                          ±21.9                                                                          ±19.6                                                                          ±19.1                                     AP.sub.syst                                                                        150.9                                                                              115.3                                                                             120.9                                                                             121.9                                                                             120.9                                                                            120.4                                                                             121.5                                                                             122.8                                             ±8.4                                                                           ±13.8                                                                          ±13.3                                                                          ±11.6                                                                          ±10.6                                                                          ±9.3                                                                           ±8.7                                                                           ±8.8                                      AP.sub.diast                                                                        88.1                                                                              74.1                                                                              82.5                                                                              83.4                                                                              83.4                                                                              80.6                                                                              79.1                                                                              80.6                                             ±7.7                                                                           ±10.0                                                                          ±9.4                                                                           ±9.4                                                                           ±8.4                                                                           ±7.7                                                                           ±6.7                                                                           ±6.6                                      PRA   3.94                                                                              2.06                                                                              2.81                                                                              2.81                                                                              2.95                                                                              3.24                                                                              3.30                                                                              3.28                                             ±0.19                                                                          ±0.45                                                                          ±0.57                                                                          ±0.45                                                                          ±0.50                                                                          ±0.54                                                                          ±0.52                                                                          ±0.41                                      ##STR12##                                                                          15.8 ±1.4                                                                      15.6 ±2.1                                                                      13.7 ±1.4                                                                      14.1 ±1.6                                                                      14.2 ± 1.6                                                                     14.0 ±1.9                                                                      13.8 ±1.7                                                                      14.0 ±1.8                                LVEDP                                                                               5.53                                                                              2.62                                                                              2.91                                                                              2.91                                                                              3.20                                                                              3.37                                                                              3.56                                                                              4.03                                             ±1.3                                                                           ±0.6                                                                           ±0.8                                                                           ±0.8                                                                           ±0.8                                                                           ±0.8                                                                           ±0.9                                                                           ±1.0                                      dp/dt                                                                               2081.2                                                                            2606.2                                                                            2343.7                                                                            2362.5                                                                            2268.7                                                                            2250.0                                                                            2231.2                                                                            2175.0                                           ±253.2                                                                         ±345.5                                                                         ±251.3                                                                         ±255.2                                                                         ±309.8                                                                         ±336.8                                                                         ±330.3                                                                         ±310.7                                    HL.sub.L                                                                            0.83                                                                              0.75                                                                              0.74                                                                              0.72                                                                              0.72                                                                              0.72                                                                              0.72                                                                              0.74                                             ±0.08                                                                          ±0.13                                                                          ±0.08                                                                          ±0.06                                                                          ±0.06                                                                          ±0.06                                                                          ±0.05                                                                          ±0.05                                     HL.sub.R                                                                            96.0                                                                              115.8                                                                             87.6                                                                              89.3                                                                              88.8                                                                              87.3                                                                              87.7                                                                              90.0                                             ±15.4                                                                          ±18.1                                                                          ±5.1                                                                           ±16.9                                                                          ±17.6                                                                          ±20.2                                                                          ±20.0                                                                          ±20.2                                     SV    38.3                                                                              25.6                                                                              26.0                                                                              25.6                                                                              26.4                                                                              29.3                                                                              30.0                                                                              31.3                                             ±3.6                                                                           ±2.6                                                                           ±4.0                                                                           ±4.1                                                                           ±3.7                                                                           ±5.0                                                                           ±4.4                                                                           ±4.6                                      BF.sub.Fem                                                                          53.4                                                                              35.3                                                                              36.6                                                                               38.6                                                                             39.5                                                                              39.9                                                                              41.2                                                                              42.2                                             ±7.5                                                                           ±4.0                                                                           ±4.0                                                                           ±4.2                                                                           ±4.3                                                                           ±5.2                                                                           ±5.3                                                                           ±5.4                                      W.sub.Fem                                                                           0.28                                                                              0.35                                                                              0.36                                                                              0.34                                                                              0.33                                                                              0.32                                                                              0.31                                                                              0.31                                             ±0.04                                                                          ±0.08                                                                          ±0.06                                                                          ±0.06                                                                          ±0.05                                                                          ±0.05                                                                          ±0.04                                                                          ±0.05                                     HZV   3.61                                                                              3.91                                                                              3.61                                                                              3.51                                                                              3.50                                                                              3.61                                                                              3.66                                                                              3.70                                             ±0.25                                                                          ±0.27                                                                          ±0.08                                                                          ±0.16                                                                          ±0.11                                                                          ±0.21                                                                          ±0.18                                                                          ±0.18                                     W.sub.AP                                                                            0.38                                                                              0.45                                                                              0.40                                                                              0.42                                                                              0.42                                                                              0.40                                                                              0.37                                                                              0.36                                             ±0.03                                                                          ±0.09                                                                          ±0.07                                                                          ±0.06                                                                          ±0.06                                                                          ±0.08                                                                          ±0.07                                                                          ±0.08                                     W.sub.TP                                                                            3.94                                                                              2.93                                                                              3.42                                                                              3.59                                                                              3.57                                                                              3.41                                                                              3.32                                                                              3.33                                             ±0.3                                                                           ±0.3                                                                           ±0.4                                                                           ±0.5                                                                           ±0.4                                                                           ±0.4                                                                           ±0.4                                                                           ±0.4                                      __________________________________________________________________________         30  40  50  60  90  120 150 180                                          __________________________________________________________________________    HF    122.7                                                                            120.7                                                                              118.7                                                                             114.2                                                                             107.5                                                                             98.7                                                                              97.5                                                                              95.5                                             ±18.5                                                                          ±17.4                                                                          ±18.3                                                                          ± 20.1                                                                         ±17.5                                                                          ±11.7                                                                          ±11.1                                                                          ±8.5                                      AP.sub.syst                                                                        122.8                                                                             126.6                                                                             131.2                                                                             133.1                                                                              136.9                                                                            143.4                                                                             147.2                                                                             143.4                                             ±8.8                                                                           ±8.8                                                                           ±8.9                                                                           ±9.8                                                                           ±10.9                                                                          ±7.2                                                                           ±7.1                                                                           ±6.2                                      AP.sub.diast                                                                        79.7                                                                              81.0                                                                              83.4                                                                              87.6                                                                              87.6                                                                              93.7                                                                              94.7                                                                              91.9                                             ±7.1                                                                           ±6.8                                                                           ±6.2                                                                           ±6.2                                                                           ±6.1                                                                           ±3.4                                                                           ±3.9                                                                           ±3.9                                      PRA   3.52                                                                              3.37                                                                              3.43                                                                              3.37                                                                              3.85                                                                              3.94                                                                              4.03                                                                              4.12                                             ±0.61                                                                          ±0.59                                                                          ±0.55                                                                          ±0.59                                                                          ±0.52                                                                          ±0.49                                                                          ±0.39                                                                          ±0.31                                      ##STR13##                                                                          14.1 ±1.8                                                                      14.1 ±1.8                                                                      13.9 ±1.9                                                                      14.1 ±2.0                                                                      14.5 ±2.1                                                                      15.1 ±2.3                                                                      15.1 ±1.5                                                                      14.9 ±1.3                                LVEDP                                                                               4.31                                                                              4.41                                                                              4.69                                                                              4.78                                                                              5.25                                                                              6.37                                                                              6.97                                                                              7.69                                             ±1.1                                                                           ±1.2                                                                           ±1.2                                                                           ±1.3                                                                           ±1.4                                                                           ±1.2                                                                           ±1.4                                                                           ±1.3                                      dp/dt                                                                               2184.4                                                                             2137.5                                                                           2118.5                                                                            2118.5                                                                            2081.2                                                                            2043.7                                                                            1950.0                                                                            1593.7                                           ±330.6                                                                         ±327.6                                                                         ±315.8                                                                         ±335.9                                                                         ±380.4                                                                         ±402.0                                                                         ±373.7                                                                         ±297.4                                    HL.sub.L                                                                            0.73                                                                              0.76                                                                              0.75                                                                              0.79                                                                              0.82                                                                              0.89                                                                              0.91                                                                              0.91                                             ±0.06                                                                          ±0.05                                                                          ±0.04                                                                          ±0.05                                                                          ±0.04                                                                          ±0.06                                                                          ±0.05                                                                          ±0.06                                     HL.sub.R                                                                            84.9                                                                              89.3                                                                              83.6                                                                              89.5                                                                              91.5                                                                              98.7                                                                              98.0                                                                              98.5                                             ±17.7                                                                          ±19.6                                                                          ±20.3                                                                          ±21.8                                                                          ±26.7                                                                          ±29.7                                                                          ±21.3                                                                          ±20.0                                     SV    31.6                                                                              32.7                                                                              32.0                                                                              35.6                                                                              37.1                                                                              40.0                                                                              41.0                                                                              42.6                                             ±4.5                                                                           ±4.5                                                                           ±4.7                                                                           ±5.8                                                                           ±4.4                                                                           ±2.7                                                                           ±3.3                                                                           ±1.9                                      BF.sub.Fem                                                                          43.9                                                                              46.3                                                                              50.6                                                                              50.4                                                                              50.8                                                                              58.6                                                                              58.2                                                                              59.4                                             ±4.9                                                                           ±4.3                                                                           ±4.5                                                                           ±5.5                                                                           ±6.6                                                                           ±7.9                                                                           ±8.1                                                                           ±6.3                                      W.sub.Fem                                                                           0.29                                                                              0.27                                                                              0.26                                                                              0.26                                                                              0.27                                                                              0.25                                                                              0.26                                                                              0.24                                             ±0.04                                                                          ±0.03                                                                          ±0.02                                                                          ±0.03                                                                          ±0.03                                                                          ±0.03                                                                          ±0.04                                                                          ±0.02                                     HZV   3.63                                                                              3.72                                                                              3.55                                                                              3.73                                                                              3.77                                                                              3.85                                                                              3.89                                                                              4.03                                             ±0.05                                                                          ±0.10                                                                          ±0.08                                                                          ±0.03                                                                          ±0.16                                                                          ±0.23                                                                          ±0.18                                                                          ±0.23                                     W.sub.AP                                                                            0.36                                                                              0.35                                                                              0.34                                                                              0.33                                                                              0.32                                                                              0.30                                                                              0.27                                                                              0.24                                             ±0.10                                                                          ±0.10                                                                          ±0.10                                                                          ±0.10                                                                          ±0.09                                                                          ±0.07                                                                          ±0.05                                                                          ±0.03                                     W.sub.TP                                                                            3.32                                                                              3.34                                                                              3.61                                                                              3.46                                                                              3.59                                                                              3.72                                                                              3.73                                                                              3.51                                             ±0.2                                                                           ±0.3                                                                           ±0.3                                                                           ±0.2                                                                           ±0.4                                                                           ±0.3                                                                           ±0.2                                                                           ±0.3                                      __________________________________________________________________________

For informing examination of acute toxicity of some of the compoundsaccording to the invention, said compounds were intravenouslyadministered in physiological saline solution to female NMRI-albino micein doses of 50, 100 and 200 mg/kg, respectively. The compounds wereinjected to at least 3 animals per dose. If no animal had yet been diedfollowing to the highest dose which was administered, no more doses ofsubstances were tested. In case of doubt, the examination was repeatedwith at least 3 more animals applying the same dose.

The rate of death within 24 hours after administration was observed.

In table VII, the determined rates of death as well as the LD₅₀ -rangesevaluated therefrom are shown.

                  TABLE VII                                                       ______________________________________                                        Compound                                                                              Frequency of death with an                                                                          Evaluated                                       according                                                                             intravenous dose of   LD.sub.50 -range                                to example                                                                            200 mg/kg 100 mg/kg  50 mg/kg                                                                             (mg/kg)                                   ______________________________________                                        3c      3/3       0/6        --     100-200                                   4b      3/3       3/3        0/3    50-100                                    5b      3/3       3/6         1/11  50-100                                    6b      3/3       3/3        0/3    50-100                                    9b      3/3       4/6        --     50-100                                      2c.sup.+                                                                            0/6       --         --     >200                                      ______________________________________                                         .sup.+ LD.sub.70 p.o. mouse = 1600 mg/kg and LD.sub.50 i.p. mouse = 540       mg/kg (534.7-545.4; according to Lichtfield and Wilcoxon).               

We claim:
 1. Theophyllinyldesoxy-1.4;3.6-dianhydrohexitol nitrates ofthe formula Ib ##STR14## as well as their physiologically acceptableacid-addition salts. 2.5-(7-Theophyllinyl)-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate, aswell as its physiologically acceptable acid-addition salts. 3.2-(7-Theophyllinyl)-2-desoxy-1.4;3.6-dianhydro-D-glucitol 5-nitrate, aswell as its physiologically acceptable acid-addition salts. 4.Pharmaceutical composition for treatment of coronary diseases,containing a compound according to claim 2, as well as conventionalcarriers and additive materials.
 5. Pharmaceutical composition fortreatment of coronary diseases containing a compound according to claim6, as well as conventional carriers and additive materials. 6.Pharmaceutical composition for treatment of coronary diseases containinga compound according to claim 7, as well as conventional carriers andadditive materials.